Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition

Thanyaluck Siriyong; Rachael M. Murray; Lucy E. Bidgood; Simon A. Young; Florence Wright; Benjamin J. Parcell; Supayang Piyawan Voravuthikunchai; Peter J. Coote

doi:10.1038/s41598-019-45550-z

Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition

Thanyaluck Siriyong, Rachael M. Murray, Lucy E. Bidgood, Simon A. Young, Florence Wright, Benjamin J. Parcell, Supayang Piyawan Voravuthikunchai, Peter J. Coote^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.

Original language	English
Article number	9098
Number of pages	13
Journal	Scientific Reports
Volume	9
DOIs	https://doi.org/10.1038/s41598-019-45550-z
Publication status	Published - 24 Jun 2019

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Peter John Coote
- pjc5st-andrews.acuk
- School of Biology - Lecturer
- Biomedical Sciences Research Complex
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Siriyong, T., Murray, R. M., Bidgood, L. E., Young, S. A., Wright, F., Parcell, B. J., Voravuthikunchai, S. P., & Coote, P. J. (2019). Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition. Scientific Reports, 9, Article 9098. https://doi.org/10.1038/s41598-019-45550-z

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title = "Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition",

abstract = "The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.",

author = "Thanyaluck Siriyong and Murray, {Rachael M.} and Bidgood, {Lucy E.} and Young, {Simon A.} and Florence Wright and Parcell, {Benjamin J.} and Voravuthikunchai, {Supayang Piyawan} and Coote, {Peter J.}",

note = "S.V. and T.S. were supported by Thailand Research Fund Senior Research Scholar (Grant Number RTA6180006). R.M. and P.C. were funded by University of St Andrews.",

year = "2019",

month = jun,

day = "24",

doi = "10.1038/s41598-019-45550-z",

language = "English",

volume = "9",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature publishing group",

}

Siriyong, T, Murray, RM, Bidgood, LE, Young, SA, Wright, F, Parcell, BJ, Voravuthikunchai, SP & Coote, PJ 2019, 'Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition', Scientific Reports, vol. 9, 9098. https://doi.org/10.1038/s41598-019-45550-z

Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition. / Siriyong, Thanyaluck; Murray, Rachael M.; Bidgood, Lucy E. et al.
In: Scientific Reports, Vol. 9, 9098, 24.06.2019.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection

T2 - enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition

AU - Siriyong, Thanyaluck

AU - Murray, Rachael M.

AU - Bidgood, Lucy E.

AU - Young, Simon A.

AU - Wright, Florence

AU - Parcell, Benjamin J.

AU - Voravuthikunchai, Supayang Piyawan

AU - Coote, Peter J.

N1 - S.V. and T.S. were supported by Thailand Research Fund Senior Research Scholar (Grant Number RTA6180006). R.M. and P.C. were funded by University of St Andrews.

PY - 2019/6/24

Y1 - 2019/6/24

N2 - The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.

AB - The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.

U2 - 10.1038/s41598-019-45550-z

DO - 10.1038/s41598-019-45550-z

M3 - Article

AN - SCOPUS:85067850417

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

M1 - 9098

ER -

Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition

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